Biocatalytic Synthesis of Chiral Compounds

The synthesis of chiral molecules by biocatalysis harnesses the exquisite stereo- and regioselectivity of enzymes to prepare enantiomerically pure compounds under mild, environmentally benign conditions. Central to this field are classes of enzymes such as oxidoreductases, transferases and lyases, which catalyse key carbon–carbon and carbon–heteroatom bond-forming reactions. Advances in protein engineering and directed evolution have yielded tailored catalysts with enhanced activity, stability and substrate scope. Coupled with innovations in cofactor regeneration—ranging from enzymatic recycling to bioelectrocatalysis—these developments enable economical and sustainable production of pharmaceuticals, agrochemicals, flavours and fragrances. Furthermore, one-pot cascade biocatalytic routes and engineered whole-cell systems streamline multistep syntheses, reduce waste and simplify downstream processing. The global significance of this research lies in its potential to replace hazardous reagents and energy-intensive processes with greener, scalable alternatives that meet stringent regulatory and economic demands.

Research from Nature Portfolio

Directed evolution of a cytochrome P450 enzyme has delivered a highly efficient ketone synthase capable of enantioselective oxidation of internal arylalkenes. Fifteen mutations, largely distal to the active site, collaboratively stabilise a reactive carbocation intermediate within a preorganised pocket, enabling thousands of turnovers and formal asymmetric hydrofunctionalisation when combined with partner biocatalysts.

A bioelectrocatalytic reactor employing a hydrogen-permeable palladium membrane has been developed for on-demand regeneration of NADH from water-derived hydride. By physically separating the electrolytic and enzymatic compartments, this design prevents cofactor degradation and allows independent optimisation of electrolysis and biocatalytic conditions, paving the way for electricity-driven chiral reductions with minimal waste.

Modular cascade biocatalysis has been demonstrated for multiple, regio- and enantioselective functionalisations of alkenes in a single pot. Engineered enzyme modules sequentially convert terminal alkenes into chiral diols, α-hydroxy acids, aminoalcohols and α-amino acids with high optical purity. This approach exemplifies how multienzyme assemblies in microbial hosts can streamline the synthesis of diverse chiral building blocks.

Biocatalytic Synthesis of Chiral Compounds publication trend

The graph below shows the total number of articles in biocatalytic synthesis of chiral compounds across all publications each year (not limited to Nature Index journals).

Technical terms

Biocatalyst: A natural or engineered enzyme used to accelerate chemical transformations with high selectivity.

Enantioselectivity: The preference of a catalyst to produce one enantiomer over its mirror image in a chiral reaction.

Cofactor: A non-protein molecule (e.g. NADH) that participates in enzymatic redox reactions and must often be regenerated.

Directed evolution: A method to improve enzyme properties by iterative rounds of mutation and selection.

Cascade biocatalysis: A series of enzyme-catalysed steps performed sequentially in one reaction vessel to build molecular complexity.

Active site preorganisation: The structural arrangement of amino acid residues in an enzyme that optimises substrate binding and catalytic efficiency.

References

1. Engineered cytochrome P450 for direct arylalkene-to-ketone oxidation via highly reactive carbocation intermediates. Nature Catalysis (2023).
2. Bioelectrocatalysis with a palladium membrane reactor. Nature Communications (2023).
3. Highly regio- and enantioselective multiple oxy- and amino-functionalizations of alkenes by modular cascade biocatalysis. Nature Communications (2016).
4. Biocatalysis: landmark discoveries and applications in chemical synthesis. Chemical Society Reviews (2024).
5. Recent Advances in ω-Transaminase-Mediated Biocatalysis for the Enantioselective Synthesis of Chiral Amines. Catalysts (2018).
6. Biocatalysis making waves in organic chemistry. Chemical Society Reviews (2022).